The present invention relates to a medicine, especially to novel fused ring compound having steroid C17,20-lyase inhibitory activity, or its production and pharmaceutical compositions containing the same.
Steroid C17,20-lyase converts 17-hydroxypregnenolone and 17-hydroxyprogesterone derived from cholesterol to androgen. Therefore, a medicine having steroid C17,20-lyase inhibitory activity suppresses the formation of androgen and estrogen which is produced from androgen, and is useful for the preventing and treating diseases whose exacerbation factor is androgen or estrogen. As the diseases whose exacerbation factor is androgen or estrogen, there may be mentioned, for example, prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis, etc.
It has been already known that some steroid type compounds and some non-steroid type compounds inhibit steroid C17,20-lyase. The steroid type compounds are disclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A 413270, etc. As non-steroid type compounds, for example, (1H-imidazol-1-yl)methyl-substituted benzimidazole derivatives are shown in Japanese Published Unexamined Patent Application No.85975/1989, carbazole derivatives are shown in WO94/27989 and WO96/14090, azole derivatives are shown in WO95/09157, and 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161.
Heretofore, steroid C17,20-lyase inhibitors which can actually be used as medicine have not been known. Thus, the early development of steroid C17,20-lyase inhibitors which are useful as medicine has been highly anticipated.
The present inventors have done extensive studies so as to find superior androgen synthetase inhibitors, especially steroid a C17,20-lyase inhibitors, and found that a compound having the formula (I) 
has superior steroid C17,20-lyase inhibiting activity because of its specific structure and that the compound has less toxicity and has good properties as medicine. The present invention has been accomplished by these findings.
The present invention relates to:
(1) A compound of the formula: 
[wherein A1 is a 5 or 6-membered ring which may be substituted by a group not containing a cyclic group, A2 is an aromatic ring which may be substituted, X is a divalent group, Y is a nitrogen atom or a methine group, Z is an ethenylene which may be substituted or ethynylene, R is a heterocyclic group which may be substituted, provided that 3,4-dihydro-6-[3-(1H-imidazol-1-yl)-1-propenyl]-2(1H)-quinolone and 2-[3-[5-ethyl-6-methyl-2-(benzyloxy)-3-pyridyl]-1-propenyl]benzoxazole are excluded.], or a salt thereof,
(2) A compound as shown in the above item (1), wherein R is a 5 or 6-membered nitrogen-containing heterocyclic group which may be substituted,
(3) A compound as shown in the above item (1), wherein R is an imidazolyl, a triazolyl or a pyridyl which may be substituted,
(4) A compound as shown in the above item (1), wherein R is an imidazolyl which may be substituted,
(5) A compound as shown in the above item (1), wherein the ring: 
is naphthalene or tetraline,
(6) A compound as shown in the above item (1), wherein the ring: 
is benzothiophene or benzofuran,
(7) A compound as shown in the above item (1), wherein the ring: 
is benzothiophene,
(8) A compound as shown in the above item (1), wherein Z is an ethenylene which may be substituted,
(9) A compound as shown in the above item (1), wherein Z is an ethenylene which may be substituted by methyl or fluorine,
(10) A compound as shown in the above item (1), wherein Z is unsubstituted ethenylene,
(11) A compound as shown in the above item (1), wherein X is a divalent hydrocarbon group which may be substituted.
(12) A compound as shown in the above item (1), wherein X is a methylene which may be substituted,
(13) A compound as shown in the above item (1), wherein X is unsubstituted methylene,
(14) A compound as shown in the above item (1), which is 1-[(E)-3-(2-naphthyl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(15) A compound as shown in the above item (1), which is 1-[(E)-3-(2-naphthyl)-2-butene-1-yl]-1H-imidazole or a salt thereof,
(16) A compound as shown in the above item (1), which is 1-[(E)-3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(17) A compound as shown in the above item (1), which is 4-[(E)-3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(18) A compound as shown in the above item (1), which is 4-[-(E)-3-(5-methoxy-3-methylbenzo[b]thiophene-2-yl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(19) A pharmaceutical composition containing a compound as shown in the above item (1),
(20) A steroid C17,20-lyase inhibitory composition containing a compound of the formula: 
[wherein A1 is a 5 or 6-membered ring which may be substituted by a group not containing a cyclic group, A2 is an aromatic ring which may be substituted, X is a divalent group, Y is a nitrogen atom or a methine group, Z is an ethenylene which may be substituted or ethynylene, R is a heterocyclic group which may be substituted.]or a salt thereof,
(21) An antitumor composition which contains a compound of the formula (Ixe2x80x2) or salt thereof,
(22) An antitumor composition containing a compound of the formula (Ixe2x80x2) or salt thereof as shown in the above item (21), wherein the antitumor composition is treating or preventing agent for breast cancer or prostate cancer,
(23) A method for treating mammal suffering from diseases whose exacerbation factor is androgen or estrogen, which comprises administering an effective amount of a compound of the formula (I) or a salt thereof;
(24) A method as shown in the above item (23) wherein the diseases whose exacerbation factor is androgen or estrogen is prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis;
(25) Use of a compound of the formula (Ixe2x80x2) or salt thereof for the production of an antitumor composition for treating diseases whose exacerbation factor is androgen or estrogen;
(26) Use as shown in the above item (25) wherein the diseases whose exacerbation factor is androgen or estrogen is prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis; and
(27) A process for producing a compound of the above item (1), which comprises reacting a compound of the formula: 
[wherein L is a leaving group, and each of the other symbols has the meanings as defined in the above item (1).] or a salt thereof with a compound of the formula:
Mxe2x80x94Rxe2x80x83xe2x80x83(III)
[wherein M is a hydrogen atom or a metal atom, and R has the meanings as defined in the above item (1).] or a salt thereof.
Examples of the xe2x80x9c5 or 6-membered ringxe2x80x9d in the xe2x80x9c5 or 6-membered ring which may be substituted by a group not containing a cyclic groupxe2x80x9d represented by A1 ring in the formula (I) include, for example, a 5 or 6-membered cyclic hydrocarbon, a 5 or 6-membered aromatic heterocyclic ring and a 5 or 6-membered non-aromatic heterocyclic ring, etc.
Examples of the 5 or 6-membered cyclic hydrocarbons include, for example, a C5-6cyclo alkane (cyclopentane, cyclohexane), a C5-6cycloalkene (cyclopentene, cyclohexene) and benzene, etc.,
The examples of the 5 or 6-membered aromatic heterocyclic groups include, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine (1,3,5-triazine, 1,2,4-triazine), etc.
The examples of the 5 or 6-membered non-aromatic heterocyclic groups include, pyrrolidine, tetrahydrofuran, thiolan, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, homopiperidine, pyrroline, imidazolidine, etc
Examples of the xe2x80x9caromatic ringxe2x80x9d in the xe2x80x9caromatic ring which may be substitutedxe2x80x9d represented by A2 in the formula (I) include, for example, phenyl, a heterocyclic ring such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine (1,3,5-triazine, 1,2,4-triazine), etc.
The fused ring compound represented by the formula: 
in the formula (I) includes, both of a cyclic hydrocarbon and a heterocyclic ring. When one of the rings (A2 ring) is an aromatic ring, the other (A1 ring) may be an aromatic ring or an aliphatic ring. Examples of the fused ring compounds include a cyclic hydrocarbon (e.g., naphthalene), a heterocyclic compound containing a nitrogen atom (indolizine, isoindole, indole, isoquinoline, quinoline, indazole, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, piridopyridine, pteridine, purine, etc.), an oxygen-containing heterocyclic ring (isochroman, chroman, benzofuran, cyclopentapyran, etc.), a sulfur-containing heterocyclic ring (benzothiophene, etc.), a heterocyclic ring containing two or more hetero atoms which are different from each other (benzothiazole, benzoxazole, thiazolopyridine, etc.), and compounds whose A1 ring is reduced (e.g., tetraline, 1,2-dihydronaphthalene, 3,4-dihydronaphthalene, indane, indene, etc.), etc. Preferable examples of the fused rings include, for example, naphthalene, tetraline, benzothiophene, benzofuran, etc.
When A1 ring has a substituent or substituents, the substituent is neither a ring nor a group containing a ring. Examples of the substituents include (1) a lower alkyl group which may be substituted, (2) a lower alkoxy group which may be substituted, (3) a carboxyl group which may be esterified, (4) a carbamoyl group which may be substituted or a thiocarbamoyl group which may be substituted, (5) an amino group which may be substituted, (6) a hydroxyl group which may be substituted, (7) a thiol (mercapto) group which may be substituted, (8) an acyl group, (9) a halogen atom (e.g., fluorine, chlorine, bromine, etc.), (10) a nitro group, (11) a cyano group, (12) an oxo group, etc. One to three of these substituents may substitute at any position.
Examples of the xe2x80x9clower alkyl groupxe2x80x9d in the xe2x80x9clower alkyl group which may be substitutedxe2x80x9d (1) include, for example, a C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.
Examples of the xe2x80x9clower alkoxy groupxe2x80x9d in the xe2x80x9clower alkoxy group which may be substitutedxe2x80x9d (2) include, for example, a C1-6alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, isohexyloxy, etc.
The lower alkyl group (1) and the lower alkoxy group (2) may have one to three substituents at any substitutable position. Examples of the substituents include, for example, a halogen (e.g., fluorine, chlorine, bromine, etc.), a lower (C1-3)alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), a hydroxyl group, an amino group which may be substituted by a lower (C1-3)alkyl (e.g., amino, methylamino, dimethylamino, diethylamino), etc.
Examples of the xe2x80x9ccarboxyl which may be esterifiedxe2x80x9d (3) include a carboxyl group, a (lower (C16)alkoxy)carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert.-pentyloxycarbonyl, hexyloxycarbonyl, etc.), etc. Among them, carboxyl, methoxycarbonyl, ethoxycarbonyl, etc., are preferable.
Examples of the substituent of the xe2x80x9ccarbamoyl group which may be substitutedxe2x80x9d or xe2x80x9cthiocarbamoyl group which may be substitutedxe2x80x9d (4) and the xe2x80x9camino group which may be substitutedxe2x80x9d (5) include, for example, a C1-6alkyl which may be substituted etc. Examples of the xe2x80x9cC1-6alkylxe2x80x9d in the xe2x80x9cC1-6alkyl which may be substitutedxe2x80x9d include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc. These substituents may be the same or different, and one or two of these substituents maybe substituted. Examples of the substituents in the xe2x80x9cC1-6alkyl group which may be substitutedxe2x80x9d include, a halogen (e.g., fluorine, chlorine, bromine, etc.), an alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkoxy group such as methoxy, ethoxy, propoxy, etc., a C1-4alkoxy group substituted by a halogen or halogens such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3, 3-pentafluoropropoxy, etc.), an alkyl group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkyl such as methyl, ethyl, propyl, etc.), nitro, etc. One to five of these substituents may be substituted.
Example of the substituents in the xe2x80x9chydroxyl group which may be substitutedxe2x80x9d (6) and the xe2x80x9cthiol group which may be substitutedxe2x80x9d (7) include, for example, a C1-6alkyl which may be substituted, etc. Examples of the xe2x80x9cC1-6alkylxe2x80x9d in the xe2x80x9cC1-6alkyl which may be substitutedxe2x80x9d include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc. The C1-6alkyl group may have 1 to 5 substituents at any substitutable position. Examples of the substituents include, for example, a halogen (e.g., fluorine, chlorine, bromine, etc.), an alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkoxy such as methoxy, ethoxy, propoxy, etc., a C1-4alkoxy which is substituted by 1 to 3 halogens such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, etc.), an alkyl group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc., a C1-4alkyl substituted by a halogen such as trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, etc.), nitro, amino, cyano, etc.
Examples of the acyl groups (8) include, for example, formyl, a carbonyl group substituted by a hydrocarbon group which may be substituted, a sulfinyl group substituted by a hydrocarbon group which may be substituted, a sulfonyl group substituted by a hydrocarbon group which may be substituted, etc. Examples of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d include, for example, a C1-6alkyl group which may be substituted, etc. That is, examples of the acyl groups include, formyl as well as a carbonyl group, a sulfinyl group and a sulfonyl group, each of which is substituted by a C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.). The C1-6alkyl may be substituted, at any substitutable position, by 1 to 5 substituents. Examples of the substituents include, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a lower alkoxy group (e.g., a C1-4alkoxy group such as methoxy, ethoxy, propoxy, etc.), a lower alkyl group (e.g., C1-4alkyl group such as methyl, ethyl, propyl, etc.), etc.
When A2 ring is substituted, examples of the substituents include, (1) a lower alkyl group which may be substituted, (2) a lower alkoxy group which may be substituted, (3) an aryl group which may be substituted, (4) a lower cycloalkyl group or a cycloalkenyl group which may be substituted, (5) a carboxyl group which may be esterified, (6) a carbamoyl group or a thio carbamoyl group which may be substituted, (7) an amino group which may be substituted, (8) a hydroxyl group which may be substituted, (9) a thiol (mercapto) group which may be substituted, (10) an acyl group, (11) a halogen atom (e.g., fluorine, chlorine, bromine, etc.), (12) a nitro group, (13) a cyano group, etc. The number of the substituent(s) may be 1 to 3.
Examples of the xe2x80x9clower alkylxe2x80x9d in the xe2x80x9clower alkyl group which may be substitutedxe2x80x9d (1) include, for example, a C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.
Examples of the xe2x80x9clower alkoxy groupxe2x80x9d in the xe2x80x9clower alkoxy group which may be substitutedxe2x80x9d (2) include a C1-6alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, isohexyloxy, etc.
Each of the lower alkyl group (1) and the lower alkoxy group (2) may have 1 to 3 substituents at any substitutable position. Examples of the substituents include, for example, a halogen ( e.g., fluorine, chlorine, bromine, etc.), a lower (C1-3)alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) a hydroxyl group, an amino group which may be substituted (e.g., amino, methylamino, dimethylamino, diethylamino), etc.
Examples of the xe2x80x9caryl groupxe2x80x9d in the xe2x80x9caryl group which may be substitutedxe2x80x9d (3) include a C6-10 aryl group such as phenyl, naphthyl, etc. Among them, phenyl is preferable.
Examples of the xe2x80x9clower cycloalkyl groupxe2x80x9d in the xe2x80x9clower cycloalkyl group which may be substitutedxe2x80x9d (4) include a C4-7cycloalkyl group such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
Examples of the xe2x80x9ccycloalkenyl groupxe2x80x9d in the xe2x80x9clower cycloalkenyl group which may be substitutedxe2x80x9d (4) include a C3-6cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.
The aryl group (3), the lower cycloalkyl group or lower cycloalkenyl group (4) may have 1 to 5 substituents, preferably 1 to 3 substituents at any substitutable position. Examples of the substituents include an alkoxy group (e.g., a C1-3alkoxy group such as methoxy, ethoxy, propoxy, etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), an alkyl group (e.g., a C1-3alkyl such as methyl, ethyl, propyl, etc.), an amino group which may be substituted by a lower (C1-3)alkyl (e.g., amino, methylamino, dimethylamino, diethylamino), a hydroxyl group, a nitro group, a cyano group, etc.
Examples of the carboxyl group which may be esterified (5) include a carboxyl group, a (lower(C1-6)alkoxy)carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert.-pentyloxycarbonyl, hexyloxycarbonyl, etc.), a (C6-10 aryl)oxycarbonyl (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl, etc.), a (C7-10aralkyl)oxycarbonyl (e.g., a (phenyl-C1-4alkyloxy)carbonyl such as benzyloxycarbonyl, etc.), etc. Among them, carboxyl, methoxycarbonyl, ethoxycarbonyl, etc. are preferable.
Examples of the substituents in the xe2x80x9ccarbamoyl group or thiocarbamoyl group which may be substitutedxe2x80x9d (6) and the xe2x80x9camino group which may be substitutedxe2x80x9d (7) include, for example, a C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl. neopentyl, hexyl, isohexyl, etc.) which may be substituted, a C3-6cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may be substituted, a C6-10 aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.) which may be substituted, a C7-12aralkyl group (e.g., a phenyl-C1-4alkyl, a naphthyl-C1-2alkyl, etc., such as benzyl, phenethyl, etc.) which may be substituted, a C6-10 arylsulfonyl group (e.g., benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.) which may be substituted, etc. These substituents may be the same or different, and one or two of these substituents may substitute at any substitutable position. Examples of the substituents in the xe2x80x9cC1-6alkyl which may be substitutedxe2x80x9d, the xe2x80x9cC3-6cycloalkyl group which may be substitutedxe2x80x9d, the xe2x80x9cC6-10 aryl group which may be substitutedxe2x80x9d, the xe2x80x9cC7-12aralkyl group which may be substitutedxe2x80x9d or the xe2x80x9cC6-10arylsulfonyl group which may be substitutedxe2x80x9d include, for example, a halogen (e.g., fluorine, chlorine, bromine, etc.), an alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkoxy such as methoxy, ethoxy, propoxy, etc., a halogeno-C1-4alkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, etc.), an alkyl group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkyl such as methyl, ethyl, propyl, etc., a halogeno-C1-4alkyl such as trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, etc.), a nitro group, etc. One to five of these substituents may substitute at any substitutable position. The nitrogen atom and two substituents on the nitrogen atom in the xe2x80x9camino group which may be substitutedxe2x80x9d (7) may together form a cyclic amino group. Examples of the cyclic amino groups include, for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, etc.
Examples of the substituents in the xe2x80x9chydroxyl group which may be substitutedxe2x80x9d (8) and the xe2x80x9cthiol group which may be substitutedxe2x80x9d (9) include, for example, a C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.) which may be substituted, a C3-6cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), which may be substituted, a C6-10 aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.) which may be substituted, a C7-12aralkyl group (e.g., a phenyl-C1-4alkyl, a naphthyl-C1-2alkyl such as benzyl, phenethyl, etc.) which may be substituted, etc. Each of the C1-6alkyl group, the C3-6cycloalkyl group, the C6-10 aryl group and the C7-12aralkyl group may have 1 to 5 substituents at any substitutable position. Examples of the substituents include, for example, a halogen (e.g., fluorine, chlorine, bromine, etc.), an alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkoxy such as methoxy, ethoxy, propoxy, etc., a C1-4alkoxy substituted by a halogen such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, etc.), an alkyl which may be substituted by 1 to 3 halogen atoms (e.g., a C1-4alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc., a C1-4alkyl substituted by a halogen such as trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, etc.), nitro, amino, cyano, etc.
Examples of the acyl groups (10) include, for example, formyl, a carbonyl group substituted by a hydrocarbon group which may be substituted, a sulfinyl group substituted by a hydrocarbon group which may be substituted, a sulfonyl group substituted by a hydrocarbon group which may be substituted, etc. Examples of the xe2x80x9chydrocarbon groupxe2x80x9d in the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d include a hydrocarbon group, for example, a C1-6alkyl group, a C3-6cycloalkyl group, a C6-10 aryl group (e.g., phenyl, naphthyl, etc.), a C7-12aralkyl group (e.g., a phenyl-C1-4alkyl, a naphthyl-C1-2alkyl, etc.), etc. That is, examples of the acyl groups include, formyl as well as a carbonyl group, a sulfinyl group and a sulfonyl group each of which is substituted by a C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.). These acyl groups may have 1 to 5 substituents at any substitutable position. Example of the substituents include, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a lower alkoxy group (e.g., a C1-4alkoxy group such as methoxy, ethoxy, propoxy, etc.), a lower alkyl group (e.g., a C1-4alkyl group such as methyl, ethyl, propyl, etc.), etc.
Examples of xe2x80x9cthe heterocyclic groupxe2x80x9d in xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d represented by R in the above formulas include, for example, an aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), each of which has at least one hetero atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, as ring-constituting atom, Among them, an aromatic heterocyclic group is preferable. Examples of the aromatic heterocyclic groups include, for example, a 5 to 7-membered aromatic heterocyclic group containing one of a sulfur atom, a nitrogen atom and an oxygen atom, a 5 or 6 -membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms and a 5 to 6-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms and one sulfur atom or oxygen atom, etc. These aromatic heterocyclic group may be condensed with a 6-membered ring containing not more than 2 nitrogen atoms, benzene ring or 5-membered ring containing a sulfur atom. Examples of the aromatic heterocyclic groups include, for example, an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl), etc.) and an aromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo(b)thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.).
Examples of the non-aromatic heterocyclic groups include a 5 to 7 membered non-aromatic heterocyclic group containing one atom selected from sulfur atom, nitrogen atom and oxygen atom, and a 3 to 7 membered non-aromatic heterocyclic group containing one nitrogen atom and not more than 3 hetero atoms (e.g., nitrogen atom, oxygen atom, sulfur atom), for example, oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl, imidazolidinyl, etc. The non-aromatic heterocyclic group may be condensed with a benzene ring, a 6-membered ring containing not more than 2 nitrogen atoms or a 5-membered ring containing a sulfur atom, etc. Examples of the fused non-aromatic heterocyclic groups include, for example, chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl, isothiochromanyl, etc.
The substituent in the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d represented by R may substitutes at any substitutable position on the heterocyclic group. One to three of these substituents may substitutes. The examples of the substituents include an alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) (e.g., a C1-4alkoxy such as methoxy, ethoxy, propoxy, etc., a C1-4alkoxy substituted by a halogen, such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), alkyl group which may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) (e.g., a C1-4alkyl such as methyl, ethyl, propyl, etc., a C1-4alkyl substituted by a halogen such as trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, etc.), a C1-3alkyl group such as methyl, ethyl, propyl, isopropyl, etc., a C1-3alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, etc., a halogen atom such as chlorine, fluorine, etc., an aryl group which may be substituted by a hydroxyl group, an amino group, a nitro group or a cyano group (e.g., aC6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.,), nitro group, etc.
The preferable examples of the xe2x80x9cheterocyclic groupxe2x80x9d in the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d represented by R include, for example, a 5 or 6-membered nitrogen-containing heterocyclic group such as imidazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, etc. Especially, imidazolyl, 1,2,4-triazolyl, pyridyl, etc. are the most preferable. Preferable examples of the substituents of the heterocyclic group include alkoxy group which may be substituted by 1 to 3 halogen atoms (e. g., fluorine, chlorine, bromine, iodine) (e.g., a C1-4alkoxy such as methoxy, ethoxy, propoxy, etc., a C1-4alkoxy substituted by a halogen such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine) or an alkyl group which may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) (e.g., a C1-4alkyl such as methyl, ethyl, propyl, etc., a C1-4alkyl substituted by a halogen such as trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, etc.), etc. The number of the substituents is preferably 1 to 3.
Examples of the divalent groups represented by X include, for example, a divalent hydrocarbon group which may be substituted, xe2x80x94NRxe2x80x2xe2x80x94 (wherein Rxe2x80x2 is a hydrogen atom or a C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, etc.), xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94CONRxe2x80x2xe2x80x94 (wherein Rxe2x80x2 has the same meaning as defined above), xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, or a lower alkylene containing one or two atoms selected from the group consisting of an oxygen atom, a nitrogen atom and sulfur atom, etc.
Examples of the divalent hydrocarbon groups in the xe2x80x9cdivalent hydrocarbon group which may be substitutedxe2x80x9d include, for example, a C1-6alkylene such as methylene, ethylene, etc., a C2-6alkenylene such as ethenylene, etc., a C2-6alkynylene such as ethynylene, etc., phenylene, naphthynylene, etc. Among them, a C1-6alkylene is preferable, and methylene is the most preferable.
Examples of the substituents of the divalent hydrocarbon group include substituents of the ring A2 mentioned above.
Examples of the lower alkylenes containing one or two atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom include, for example, a C1-4alkylene group containing one or two atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom such as xe2x80x94CH2Oxe2x80x94, xe2x80x94OCH(CH3)xe2x80x94, xe2x80x94CH2CH2Oxe2x80x94, xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94NHCH(CH3)xe2x80x94, xe2x80x94N(CH3)CH2xe2x80x94, xe2x80x94NHCH2CH2NHxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94SCH(CH3)xe2x80x94, xe2x80x94CH2CH2Sxe2x80x94, xe2x80x94SCH2Sxe2x80x94, xe2x80x94SCH2CH2Sxe2x80x94, xe2x80x94OCH2CH2NHxe2x80x94, xe2x80x94OCH2CH2Sxe2x80x94, xe2x80x94SCH2CH2NHxe2x80x94, etc.
Examples of the ethenylene which may be substituted represented by Z include, for example, a group of the formula:
xe2x80x83xe2x80x94CR1=CR2xe2x80x94
(wherein, R1 and R2 each is a hydrogen atom, a fluorine atom, a lower alkyl group which may be substituted, a lower alkoxy group which may be substituted, an aryl group which may be substituted, a lower cycloalkyl group which may be substituted, or a cycloalkenyl group which may be substituted, a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted, an amino group which may be substituted, an acyl group, a halogen atom, a nitro group or a cyano group).
Examples of the lower alkyls which may be substituted, the lower alkoxy group which may be substituted, the aryl group which may be substituted, the lower cycloalkyl group which may be substituted, the cycloalkenyl group, the carboxyl group which may be esterified, the carbamoyl group which may be substituted, thio carbamoyl group which may be substituted, the amino group which may be substituted, the acyl group, the halogen, the nitro group and the cyano group represented by R1 and R2 includes those mentioned as the substituents of the ring A2.
Preferable examples of the compounds of the formula (I) include, for example, a compound of the formula: 
(wherein, R1 and R2 have the same meanings as defined above, R3 and R4 each is a hydrogen atom, a lower alkyl which may be substituted, a lower alkoxy group which may be substituted, an aryl group which may be substituted, a lower cycloalkyl group or a cycloalkenyl group which may be substituted, a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a thio carbamoyl group which may be substituted, an amino group which may be substituted, an acyl group, a halogen, a nitro group or a cyano group), etc.
As the lower alkyl which may be substituted, the lower alkoxy group which may be substituted, the aryl group which may be substituted, the lower cycloalkyl group which may be substituted, or the cycloalkenyl group, the carboxyl group which may be esterified, the carbamoyl group which may be substituted, the thiocarbamoyl group which may be substituted, the amino group which may be substituted, the acyl group, the halogen, the nitro group and the cyano group represented by R1, R2, R3 and R4, those mentioned as the substituents of the ring A2 can be used.
Preferable examples of the compounds of the formulas (I-a) and (I-b) include, for example, a compound of the formulas (I-a) and (I-b) wherein R1, R2, R3 and R4 each is a hydrogen atom and a lower alkyl group which may be substituted, R is imidazolyl or pyridyl, etc. and the most preferable examples include a compound of the formulas (I-a) and (I-b) wherein R1 and R2 each is a hydrogen atom, or a C1-3alkyl group such as methyl, ethyl, propyl, isopropyl, etc., R3 and R4 each is a hydrogen atom, and R is imidazolyl or pyridyl.
The fused ring derivatives represented by the formula (I) of the present invention may form a salt. As the salt, an acid addition salt, for example, a salt of an inorganic acid (for example, a hydrochloric acid salt, a sulfuric acid salt, a hydrobromic acid salt, a phosphoric acid salt, etc. a salt of an organic acid (for example, a acetic acid salt, a trifluoro an acetic acid salt, a succinic acid salt, a maleic acid salt, a fumaric acid salt, a propionic acid salt, a citric acid salt, a tartaric acid salt, an oxalic acid salt, a lactic acid salt, an an oxalic acid salt, a methane sulfonic acid salt, a p-toluene sulfonic acid salt, etc.), etc., a salt with a base ( for example, an alkali metal salt such as a potassium salt, a sodium salt, a lithium salt, etc., an alkaline earth metal salt such as a calcium salt, a magnesium salt, etc., an ammonium salt, a salt of organic base such as a trimethyl amine salt, a triethyl amine salt, a tert-butyldimethyl amine salt, a dibenzylmethyl amine salt, a benzyldimethyl amine salt, a N,N-dimethyl aniline salt, a pyridine salt, a quinoline salt, etc.).
The derivative of the fused ring compound of the formula (I) or (Ixe2x80x2) or the salt thereof may be hydrated.
Compound (I) and (Ixe2x80x2) of the present invention may have one or more carbon-carbon double bonds in the molecule. The cis form (Z-form) and trans form (E-form) of geometrical isomers caused by the carbon-carbon double bond are included in the present invention. Compound (I) or (Ixe2x80x2) of the present invention may have one or more asymmetric carbon in the molecule, and R-configuration and S-configuration as to the asymmetric carbons are also included in the present invention.
Compound (I) can be produced, for example, by the following methods. The following is the abbreviated figure of the reaction scheme, and each symbol in the abbreviated figure has the same meaning as defined above. All the compounds (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) are included in the compound (I) of the present invention.
The starting compound and the intermediates can be used as a free form or a salt thereof like Compound (I). The reaction mixture as it is or the compound isolated by a known method from the reaction mixture can be used for the following reaction. 
[wherein R5 and R6 each is a hydrogen atom or an alkyl (a C1-6lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.); R7 is an alkyl (a C1-6lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.) or an aralkyl group such as benzyl, etc.; M is a hydrogen atom, an alkali metal, an alkaline earth metal, copper, etc.; L is a leaving group ( for example, a halogen atom, methane-sulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.); each of the other symbols has the same meaning as defined above.]
The compound (IIb) can be synthesized by subjecting Compound (IIa) to a Wittig type reaction (for example, Wittig reaction, Horner-Emmons reaction, etc.). Examples of the reagents used in a Wittig type reaction include, for example, a phosphonium salt such as a tri phenyl alkylphosphonium salt, etc., Horner-Emmons-type Wittig reagent such as a dimethoxyphosphorylalkyl, a diethoxyphosphorylalkyl, etc., The reagent is used in an amount of 1 to 10 moles, preferably 1 to 3 moles per mole of the starting compound(IIa). The reaction is usually carried out in an organic solvent which does not disturb the reaction. Examples of the organic solvents include, for example, a saturated hydrocarbon such as hexane, pentane, etc., an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., a halogenated hydrocarbon such as dichloromethane, chloroform, etc., an ether such as diethyl ether, dioxane, tetrahydrofuran, etc., an ester such as methyl acetate, ethyl acetate, etc., a nitrile such as acetonitrile, propionitrile, etc., a nitro compound such as nitromethane, nitroethane, etc., an aromatic hydrocarbon such as benzene, toluene, etc. These solvents can be used solely or in combination of two or more kind of solvent. The reaction is usually carried out in the presence of a base. Examples of the bases include an alkali metal hydride, an organic alkali metal, an alkali metal alkoxide, etc. The base is used in an amount of about 1 to 5 mole per mole of the starting compound. The reaction mixture is usually xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C.xcx9c50xc2x0 C., and the reaction time is about 5 minutes to 5 hours.
The ester compound (IIb) is reduced to produce Compound (IIc). Examples of the reducing agents which can be used include, for example, diisobutylaluminum hydride, lithium aluminum hydride, etc. The amount of the reducing agent is about 1 to 5 moles, preferably about 1 to 2 moles per mole of Compound (IIb) though it depends on the kind of the reducing agent used. The reaction is advantageously carried out in a solvent which is not disturb the reaction. Preferable examples of the solvents include, for example, an ether such as tetrahydrofuran, etc., a halogenated hydrocarbon such as dichloromethane, etc., a hydrocarbon such as hexane, toluene, etc. though it is not limited as long as the reaction proceeds.
The reaction time varies depending on the activity of the reducing agent used and the amount of the reducing agent, but usually is 30 minutes to 24 hours, preferably 30 minutes to 10 hours. The reaction temperature is usually xe2x88x9278xc2x0 C. to 30xc2x0 C.
Then compound (IIc) is reacted with a reagent such a sulfonyl chloride as thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, etc. to form Compound (IId). The reagent is usually used in an amount of 1 to 10 mole per mole of the starting compound. The reaction is usually carried out in the presence of a base. As the base, for example, an alkali metal, an alkali metal hydride, a tertiary amine such as diisopropylethylamine, 2,6-di-tert-butylpyridine, 2,6-di-tert-butyl-4-methylpyridine, triethylamine, etc., can be used. The amount of the base used is about 1 to 5 moles per mole of the starting compound. The reaction is usually carried out in an organic solvent which does not influence the reaction. As the organic solvent, for example, a saturated hydrocarbon such as hexane, pentane, etc., a halogenated hydrocarbon such as dichloromethane, etc., an ether such as diethyl ether, dioxane, tetrahydrofuran, etc., an ester such as methyl acetate, ethyl acetate, etc., an aromatic hydrocarbon such as benzene, toluene, etc., can be used. These solvents can be used solely or in combination with two or more in an appropriate ratio. The reaction temperature is usually xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 50xc2x0 C. The reaction time is 5 minutes to 5 days. The compound (IId) can also be produced by reacting Compound (IIc) with a reagent, for example, carbon tetrabromide, carbon tetrachloride, etc., in the presence of triphenylphosphine, etc. The reaction can be carried out by a known method, for example, J. Org. Chem., 42, 353(1977), etc., or a method similar to the known method.
The compound (Ia) can be produced by reacting Compound (IId) with a compound of the formula: Mxe2x80x94R. The amount of the compound Mxe2x80x94R is about 1 to 10 moles per mole of Compound (IId). The reaction is usually carried out by using a solvent which is inert to the reaction. As the solvent, for example, an ether such as dimethylformamide, tetrahydrofuran, etc., a halogenated hydrocarbon such as dichloromethane, etc., are mentioned. The reaction time varies depend on the activity of the compound Rxe2x80x94M and its amount, but usually is 30 minutes to 24 hours, preferably 30 minutes to 10 hours. The reaction temperature is usually xe2x88x9278xc2x0 C. to 150xc2x0 C. 
[wherein Rxe2x80x25 and R8 each is a hydrogen atom or an alkyl (e.g., an alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., and each of the other symbols has the same meaning as defined above].
Compound (IIIb) can be produced by subjecting Compound (IIa) and Compound (IIIa) to the known aldol reaction, followed by dehydration reaction. The reaction is usually carried out in the presence of an acid or a base. As the base, for example, potassium hydroxide, sodium methoxide, potassium tert-butoxide, LDA (lithium diisopropylamide), an alkali metal hydride, etc., can be used. The amount of the base is about 0.01 mole to 5 moles per mole of the starting compound. As the acid, for example, hydrochloric acid, sulfuric acid, p-toluene sulfonic acid, etc., can be used. The amount of the base is about 0.01 mole to 5 moles per mole of the starting compound. The reaction is usually carried out in an organic solvent which does not influence the reaction. Examples of the organic solvents which does not influence the reaction include, for example, a saturated hydrocarbon such as hexane, pentane, etc., a halogenated hydrocarbon such as dichloromethane, etc., an ether such as diethyl ether, dioxane, tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, toluene, etc., an alcohol such as methanol, ethanol, etc. These solvents can be used solely or in combination of two or more kinds of solvent. The reaction temperature is usually xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 50xc2x0 C. The reaction time is usually 5 minutes to 10 hours.
Then Compound (IIIb) is subjected to the reduction reaction to produce Compound (IIIc). The reaction is usually carried out in the presence of a reducing catalyst and hydrogen without a solvent or in a suitable solvent. It is preferable to use the reducing agent in an amount of about 0.01 to 100 weight %, preferably about 0.01 to 50 weight % per mole of Compound (IIIb). As the catalytic reduction agent, palladium-black, palladium-carbon, platinum oxide, platinum black, Raney nickel, Raney cobalt, etc., can be mentioned. It is advantageous to use a solvent inert to the reaction in the present reaction. As the solvent, for example, water, an alcohol such as methanol, ethanol, propanol, etc., an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., a hydrocarbon such as benzene, toluene, cyclohexane, etc., an ester such as ethyl acetate, etc., an organic acid such as acetic acid, etc. can be used, though it is not limited as long as the reaction proceeds. These solvents can be used solely or in combination of two or more kinds of solvent. The reaction time varies depending on the activity of the reducing catalyst used and the amount of the reducing catalyst, but usually is 0.5 hour to 24 hours, preferably 0.5 hour to 5 hours. The reaction temperature is usually 0xc2x0 C. to 120xc2x0 C., preferably 10xc2x0 C. to 70xc2x0 C.
Then ketone compound (IIIc) is subjected to reduction reaction to produce Compound (IIId). As the reducing agent used, for example, sodium borohydride, lithium aluminum hydride, lithium tri-t-butoxyaluminum hydride, lithium tri-sec-butylboro hydride, etc., may be mentioned.
The amount of the reducing agent used is about 1 to 4 moles, preferably about 1 mole per mole of Compound (IIIb). The reaction is advantageously carried out in an solvent which is inert to the reaction. As the solvent, for example, an ether such as tetrahydrofuran, etc., a halogenated hydrocarbon such as dichloromethane, etc., an alcohol such as methanol, etc., a hydrocarbon such as hexane, toluene, etc., are preferable, though it is not limited as long as the reaction proceeds. The reaction time varies depend on the activity of the reducing agent used and the amount of the reducing agent, but usually is 5 minutes to 24 hours, preferably 5 minutes to 5 hours. The reaction temperature is usually xe2x88x9278xc2x0 C. to 30xc2x0 C.
Then, Compound (IIId) can be converted to Compound (IIIe) by a similar manner to the reaction converting Compound (IIc) to Compound (IId).
Furthermore Compound (Ib) can be produced by subjecting Compound (IIIe) to 1,2-elimination reaction. The reaction is usually carried out in the presence of a base. As the base, potassium hydroxide, sodium methoxide, collidine, potassium tert-butoxide, diisopropylethylamine, DBU (1,8-Diazabicyclo(5.4.0)undec-7-ene), etc., can be used. The reaction is advantageously carried out in a solvent inert to the reaction. The base itself can be used as a solvent. As the solvent, for example, an ether such as tetrahydrofuran, etc., a halogenated hydrocarbon such as dichloromethane, etc., a hydrocarbon such as dimethylsulfoxide, hexane, toluene, etc., are preferable though it is not limited as long as the reaction proceeds. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 5 hours. The reaction temperature is usually 0xc2x0 C. to 200xc2x0 C. 
[wherein G is a hydrogen atom, B(ORxe2x80x3)2, SnRxe2x80x33, AlRxe2x80x32 [Rxe2x80x3 is an alkyl group (e.g., an alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.], MgX, ZnX (X is a halogen atom such as chlorine, bromine, etc.), R9, R10, R11 and R12 each is a hydrogen atom or an alkyl group (e.g., a lower alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., ), and each of the other symbols has the same meaning as defined above.]
Compound (IVc) can be produced from Compound (IVa) by a reaction which forms a bond between a carbon atom and a carbon atom (for example, Heck reaction, Suzuki reaction, etc.) by using ethylene compound (IVb) and a transition metal ( for example, palladium catalyst, etc.). The reaction is carried out by a known method, for example, method shown in J. Org. Chem., 37, 2320 (1972), Tetrahedron, 50, 2003 (1994), etc., or a similar manner to the known methods.
Further, Compound (Ic) can be produced from Compound (IVc) by a similar manner to the reaction which converts Compound (IIc) to 
[wherein each symbol has the same meaning as defined above.]
Compound (Vb) can be produced by subjecting Compound (IVa) and Compound (Va) to, for example, the reaction which forms carbon-carbon bond by using palladium catalyst, etc. The reaction is carried out by a known method, for example, reaction shown in Jikkenkagaku-koza 25(VII),404(1991), etc., or a manner similar to those.
Then Compound (Vb) is subjected by reduction reaction to produce Compound (Vc). The reaction is usually carried out in the presence of a reducing catalyst and hydrogen without a solvent or in a suitable solvent. The reducing catalyst is used in an amount of about 0.01 to 50 weight %, preferably about 0.01 to 25 weight % per mole of Compound (Vb). Examples of the reducing catalyst include palladium-black, palladium-carbon, palladium-barium sulfate, palladium-calcium carbonate, etc. In the reaction, the reducing catalyst may be used after reducing the activity of catalyst with an amine such as quinoline, pyridine, etc., a heavy metal such as lead, etc., a sulfur compound, etc. It is advantageous to use a solvent inert to the reaction in the present reaction. Examples of the solvents include, for example, water, an alcohol such as methanol, ethanol, propanol, etc., an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., a hydrocarbon such as benzene, toluene, cyclohexane, etc., an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., a nitrile such as acetonitrile, propionitrile, etc., an ester such as ethyl acetate, etc. an organic acid such as formic acid, acetic acid, etc., though it is not limited as long as the reaction proceeds. These solvents can be used solely or in combination of two or more kind of solvent. The reaction time is usually 0.5 hour to 96 hours, preferably 0.5 hour to 10 hours though it varies activity and amount of the reducing agent used. The reaction temperature is usually 0xc2x0 C. to 120xc2x0 C., preferably 10xc2x0 C. to 70xc2x0 C.
In the reduction reaction, for example, lithium aluminum hydride, Red-A1 (NaALH2(OCH2CH2OCH3)2), diisobutyl aluminum hydride, etc., may be used as the reducing agent. Further, the reaction may be carried out in the presence of a base. Examples of the bases include, for example, sodium methoxide, n-butyl lithium, etc. The amount of the reducing agent is usually about 1 to 4 moles, preferably about 1 mole per mole of Compound (Vb). It is advantageous to use a solvent inert to the reaction in the present reaction. As the solvent is mentioned, for example, an ether such as tetrahydrofuran, etc., a halogenated hydrocarbon such as dichloromethane, etc., an alcohol such as methanol, etc., a hydrocarbon such as hexane, toluene, etc., though it is not limited as long as the reaction proceeds. The reaction time varies depending on the activity of the reducing agent used and the amount of the reducing agent, but usually is 30 minutes to 24 hours, preferably 30 minutes to 10 hours. The reaction temperature is usually xe2x88x9278xc2x0 C.xcx9c100xc2x0 C.
Furthermore, Compound (Id) can be produced from Compound (Vc) by a similar manner to the reaction in which Compound (Ia) is synthesized from Compound (IIc). By a similar manner, Compound (Ie) can be produced from Compound (Vb). 
[wherein L1 is a hydrogen atom or a leaving group (e.g., a halogen atom, etc.), R13 is a lower alkyl group (e.g., an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl, sec-butyl, t-butyl, etc.), Z is a lithium atom or Mgxe2x80x94X (X is a halogen atom such as chlorine, bromine, etc.), and each of the other symbols has the same meaning as defined above.]
Compound (Vg) can be produced by introducing Compound (IVaxe2x80x2) to Compound (Ve) by using a metal compound R13xe2x80x94Z1, followed by reacting Compound (Ve) with a carbonyl compound (Vf). The reaction can be carried out by a per se known manner, for example, a manner shown in Shin-jikkenkagaku-koza Vol. 14, p511 (Maruzen Co. Japan) or a manner similar to these methods.
Further, Compound (If) can be produced from Compound (Vg) by a similar manner to the method which introduces Compound (IIId) to Compound (Ib). Compound (If) can also be produced by treating Compound (Vg) under acidic condition. Examples of the acids used include hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, etc. The reaction can be carried out in an solvent inert to the reaction. Examples of the solvents include an ether (e.g., tetrahydrofuran, diethoxyethane, etc.), a hydrocarbon (e.g., an aromatic hydrocarbon such as benzene, toluene, xylene, etc.). The reaction time is usually 5 minutes to 48 hours. The reaction temperature is usually 0xc2x0 C. to 200xc2x0 C., preferably 40xc2x0 C. to 120xc2x0 C. 
[wherein each symbol has the same meaning as defined above.]
The carbonyl compound (VIc) can be produced by subjecting Compound (VIa) and Compound (VIb) to a known Friedel-Crafts reaction, for example, a manner shown in Shin-jikkenkagaku-koza Vol. 14, p511 (Maruzen Co. Japan) or a manner similar to these methods. Compound (VId) can be produced from Compound (VIc) by a similar manner to the reaction in which Compound (IId) is introduced to Compound (Ia). Then Compound (VIe) can be produced from Compound (VId) by a similar manner to the reaction in which Compound (IIIc) is introduced to Compoud (IIId). Then Compound (Ig) can be produced from Compound (VIe) by a similar reaction in which Compound (Vg) is introduced to Compound (If).
When the desired compound is obtained in free form, the compound may be converted to a salt by a conventional manner. When the desired compound is obtained as a salt, the compound can be converted to free form by a conventional manner. Compound (I) thus obtained can be isolated from the reaction mixture and purified by a known procedure such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. In the above reactions, an amino group, a carboxyl group, a hydroxy group, each of which is not involved in the reaction, in the compound or a salt thereof which is to be reacted may be protected. The protection with a protecting group and deprotection can be carried out by a known manner. Examples of the protecting groups of an amino group include, for example, formyl, a C1-6alkylcarbonyl (for example, acetyl, propionyl, etc.), a phenyl carbonyl, a C1-6alkyl-oxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, a C7-10aralkyloxycarbonyl (for example, a phenyl-C1-4alkyloxy-carbonyl such as benzyloxycarbonyl, etc.), trityl, phthaloyl or N,N-dimethylaminomethylene, etc., each of which may be substituted. Examples of the substituents include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, a C1-6alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), nitro, etc. The number of substituents is about 1 to 3.
Examples of the protecting groups of a carboxyl group include, for example, a C1-6alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl or silyl, etc., each of which may be substituted. Examples of the substituents include, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, a C1-6alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), nitro, etc. The number of substituents is about 1 to 3.
Examples of the protecting groups of the hydroxy group include, for example, a C1-6alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, a C7-10aralkyl (for example, a phenyl-C1-4alkyl such as benzyl, etc.), formyl, a C1-6alkyl-carbonyl (for example, acetyl, propionyl, etc.), phenyloxycarbonyl, benzoyl, a (C7-10aralkyloxy)carbonyl (for example, a phenyl-C1-4alkyloxy-carbonyl such as benzyloxycarbonyl, etc.), pyranyl, furanyl or silyl, etc., each of which may be substituted. Examples of the substituents include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a C1-6alkyl (for example, methyl, ethyl, propyl, etc.), phenyl, a C7-10aralkyl (for example, a phenyl-C1-4alkyl such as benzyl, etc.), nitro, etc. The number of substituents is about 1 to 4.
The deprotection reaction is carried out by a known manner or a similar manner thereof. Examples of the deprotection reactions include a manner treating with, for example, acid, base, reduction, ultraviolet ray, hydrazine, phenyl hydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
When Compound (I) is diastereomer, conformer, etc., Compound (I) can be isolated and purified by a isolation procedure or purification procedure mentioned above, if. desirable. When Compound (I) is a racemate, (+)-form and (xe2x88x92)-form of Compound (I) can be isolated by a usual optical resolution procedure. When Compound (I) has a basic group, it can be converted to a salt with an acid by a known manner.
Compound (I) and (Ixe2x80x2) has superior effect for medicine, and especially has a superior inhibitory activity of steroid C17,20-lyase. Compound (I) and (Ixe2x80x2) is less toxic and has little adverse side effect. Compound (I) and (Ixe2x80x2) is useful for the preventing and treating a mammal (for example, humans, bovines, horses, dogs, cats, monkeys, mice, rats, etc., especially humans) suffering from various disease such as (1) primary cancer of malignant tumor (for example, prostate cancer, breast cancer, uterine cancer, ovarian cancer, etc.), and its metastasis and recurrence, (2) various symptoms accompanied with these cancer (for example, pain, cachexia, etc.), (3) prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterus myoma, adenomyosis of uterus, mastopathy, polycystic ovary syndrome, etc.
While Compound (I) and (Ixe2x80x2) has a superior effect when used alone, the effect can be promoted by using the compound (I) and (Ixe2x80x2) in combination with other medicaments and remedies. Examples of the medicaments and remedies, include but are not limited to, for example, a sex hormone, an alkylating agent, an antimetabolite, an antitumor antibiotic, a plant alkaloid, an immunotherapy, etc.
Examples of the hormone-like agents include, for example, Fosfestrol, Diethylstilbestrol, chlorotrianisene, Medroxyprogesterone acetate, Megestrol acetate, Chlormadinone acetate, Cyproterone acetate, antiestrogens (for example, Tamoxifen, Toremifene citrate, etc.), LH-RH agonist (for example, Goserelin acetate, Buserelin, Leuprorelin, etc.), Droloxifene, Epitiostanol, Ethinylestradiol sulfonate, LHxe2x80x94RH antagonist (for example, Cetrorelix, Ganirelix, etc.) aromatase inhibitors (for example, Fadrozole, Anastrozole, Letrozole, Exemestane, Vorozole, Formestane, etc.), 5xcex1-reductase inhibitors (for example, Finasteride, etc.), anti-androgens (for example, Flutamide, Bicalutamide, etc.), Retinoid and suppressing agents of Retinoid metabolism (for example, Liarozole, etc.), etc.
Examples of the alkylating agents include, for example, Nitrogen mustard, Nitrogen mustard N-oxide hydrochloride, Chlorambucil, Cyclophosphamide, Ifosfamide, Thiotepa, Carboquone, Improsulphan tosilate, Busulfan, Nimustine, Mitobronitol, Melphalan, Dacarbazine, Ranimustine, Estramustine phosphate sodium, Triethylenemelamine, Carmustine, Lomustine, Streptozocin, Pipobroman, Ethoglucid, Carboplatin, Cisplatin, Miboplatin, Nedaplatin, Oxaliplatin, Altretamine, Ambamustine, Dibrospidium chloride, Fotemustine, Prednimustine, Pumitepa, Ribomustin, Temozolomide, Treosulfan, Trofosfamide, Zinostatin stimalamer, etc.
Examples of the antimetabolites include, for example, Mercaptopurine, Thioinosine, Methotrexate, Enocitabine, Cytarabine, Cytarabine ocfosfate, Ancitabine hydrochloride, 5-FU analogues (for example, Fluorouracil, Tegafur, UFT, Doxifluridine, Carmofur, Furtulon, Neofurtulon etc.), Aminopterin, Leucovorin calcium, Tabloid, Butocin, Calcium folinate, Calcium levofolinate, Cladribine, Emitefur, Fludarabine, Gemcitabine, Hydroxycarbamide, Pentostatin, etc.
Example of antitumor antibiotics include, for example, Actinomycin D, Actinomycin C, Mitomycin C, Chromomycin A3, Bleomycin hydrochloride, Bleomycin sulfate, Peplomycin sulfate, Daunorubicin hydrochloride, Doxorubicin hydrochloride, Aclarubicin hydrochloride, Pirarubicin hydrochloride, Epirubicin hydrochloride, Neocarzinostatin, Mithramycin, Sarkomycin, Carzinophilin, Mitotane, Zorubicin hydrochloride, Mitoxantrone hydrochloride, Taxol, etc.
Examples of the plant alkaloids include, for example, Etoposide, Etoposide Phosphate, Vinblastine sulfate, Vincristine sulfate, Vindesine sulfate, Teniposide, Paclitaxel, Vinorelbine, etc.
Examples of the immunotherapies (BRM) include, for example, Picibanil, Krestin, Sizofiran, Lentinan, Ubenimex, Interferons, Interleukins, Macrophage-colony stimulating factor, granules stimulating factor of spheroid colony, Erythropoietin, Lymphotoxin, BCG vaccine, Corynebacterium parvum, Levamisole, Polysaccharide-K, Procodazol, etc.
Others include L-asparaginase, Aceglatone, Procarbazine hydrochloride, Doxorubicin, Protoporphyrin, Hematoporphyrin, topoisomerase I inhibitors (for example, Irinotecan, etc.), topoisomerase II inhibitors (for example, Retinoid, Vitamin D, etc.), inhibitor of proliferation factor (for example, Suramin, etc.), xcex1-broker (for example, Tamsulosin hydrochloride, etc.), Angiogenesis inhibitors, etc.
Therapies other than chemotherapies, such as an operation including orchidectomy, thermotherapy, radiotherapy, etc., can be conducted together with the administration of Compound (I) and (Ixe2x80x2).
Examples of the pharmaceutically acceptable carriers include various organic or inorganic carriers which are used as a pharmaceutical ingredients. Exipients, lubricants, binders, disintegrators, thickeners can be used for solid preparations; solvents, dispersants, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents, etc., can be used for liquid preparations. If necessary, additives such as preservatives, antioxidants, coloring agents, sweetening agents, etc., can be used. Examples of the preferable exipients include, for example, lactose, saccharose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc. Examples of the preferable lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc. Examples of the preferable binders include, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrolidone, etc. Examples of the preferable disintegrators include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, crosscarmelose sodium, carboxymethyl starch sodium, etc. Examples of the preferable thickeners include, for example, natural rubbers, cellulose derivatives, acrylic acid polymers, etc. Examples of the preferable solvents include, for example, water for injection, alcohol, propyleneglycol, Macrogol, sesame oil, corn oil, etc. Examples of the preferable dispersants include, for example, Tween 80, HCO 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, etc. Examples of the preferable solbilizing agents include, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Examples of the preferable suspending agents include, for example, a surfactant such as stearyl triethanolamine, sodium laurylsulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; for example, hydrophilic polymer such as polyvinylalcohol, polyvinyl pyrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. Examples of the preferable isotonic agents include, for example, sodium chloride, glycerin, D-mannitol, etc. Examples of the preferable buffer agents include, for example, buffer solution such as phosphoric acid salt, acetic acid salt, carbonate, citric acid salt, etc. Examples of the preferable soothing agents include, for example, benzyl alcohol, etc. Examples of the preferable preservatives include, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc. Examples of the preferable antioxidants include, for example, sulfurous acid salt, ascorbic acid, etc.
The pharmaceutical preparation of the present invention can be manufactured by the usual manner. The ratio of Compound (I) and (Ixe2x80x2) contained in a pharmaceutical preparation is usually 0.1 to 100% (w/w). Examples of the embodiments of the pharmaceutical preparation are as follows:
(1) Tablets, Powder, Granules, Capsules
These preparations can be prepared by adding, for example, exipients, disintegrators, binders or lubricants, etc., to Compound (I) and (Ixe2x80x2), by compressive molding the mixture and, if necessary, by coating for masking of taste, enteric or sustained release.
(2) Injections
These preparations can be prepared by dissolving Compound (I) and (Ixe2x80x2) in aqueous injection together with, for example, dispersants, preservatives, isotonic agents, etc., or by dissolving, dispersing or emulsifying Compound (I) and (Ixe2x80x2) in a vegetable oil such as olive oil, sesame oil, cotton seed oil, corn oil, etc., or propyleneglycol, etc., to give an oily injection.
(3) Suppositories
These preparations can be produced by preparing a liquid composition containing Compound (I) and (Ixe2x80x2), which may be oily, aqueous solid like or aqueous semisolid like. Examples of the oily bases used for the composition include, for example, triglycerin ester of long-chain fatty acid (for example, cacao butter, witepsols, etc.), middle-chain fatty acid (for example, migriols, etc.), vegetable oils (for example, sesame oil, soybean oil, cotton seed oil, etc.), etc. Examples of the aqueous gel bases include, for example, natural rubber, cellulose derivative, vinyl polymer, acrylic acid polymer, etc.
The content of Compound (I) and (Ixe2x80x2) in these preparation is usually 0.01 to 50%, though it varies depending upon the kind of pharmaceutical preparation.
The rate of the compound of the present invention in the above pharmaceutical preparation, varies depending upon the compound used, kind of animal to which the compound is administered, number of administration times, etc. The daily dose of the compound of the present invention, for example, for adult humans suffering from solid tumors (a patient suffering from, for example, prostate cancer), is usually about 0.001 to about 500 mg/kg-weight, preferably about 0.1 to about 40 mg/kg-weight, more preferably about 0.5 to about 20 mg/kg-weight. When Compound (I) and (Ixe2x80x2) is non-orally administered or when it is administered in combination with another anti-cancer agent, Compound (I) and (Ixe2x80x2) is administered in a smaller amount mentioned then above. The actual dose of Compound (I) and (Ixe2x80x2) administered are decided by a doctor by taking the kind of compound, type of pharmaceutical preparation, age of the patient, body weight, sex, degree of disease, administration route, administration term and its interval, etc., into consideration, and the dose may be changed by a doctor.
The pharmaceutical preparation can be administered orally or parenterally. Examples of the parenteral administration routes include intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal and intraperitoneal, etc.
The above mentioned administration term and administration interval vary depending upon the various conditions and are decided by a doctor. As the administration, there may be mentioned divided administration, daily administration, intermittent administration, high dose administration therapy in short term, repeat administration, etc. It is preferable to administer the compound, for example, once to several times a day (especially two or three times a day). It is possible to administer the compound once to several times a day when using oral administration. It is also possible to administer the compound as a sustained release preparation. It is also possible to administer the compound by intravenous drip infusion over a long time.
The present invention is hereinafter described in more detail by means of the following Examples, pharmaceutical preparations and Experimental Examples, but these are merely described as examples and they are not intended to limit the present invention. The meanings of the following abbreviated symbols are as follows.
s:singlet, d:doublet, t:triplet, q:quartet, dd:double doublet, dt:double triplet, m:multiplet, br:broad, J:coupling constant, room temperature: 0xcx9c30xc2x0 C., DMF:dimethylformamide, THF:tetrahydrofuran.